Chiral Pharmacology

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CHIRAL PHARMACOLOGY

Md akbar

M Pharm (Pharmacology)

2nd semester

Jamia Hamdard

New Delhi



Introduction

In simple terms,chirality is “handedness”-that is ,theexistance of left/right opposition.for example,our left andright hand are mirror image but cant be superimposableand therefore they are “chiral”(enantiomer)

The term chiral was coined by Lord Kelvin.

While the concept of “asymmetry were developed by

J.h.vant Hoff and j.a. le bel in 1874 followed by louisPasteur.



Enantiomer • These are compounds that have the same molecular

formula and the same funtional groups bonded inthesamefashion,butwhich differ in the three dimensional(3d)arrangement of their atoms or group.

Chiral compound should have at least one asymmetriccarbon atoms in the molecule.

A carbon atom is said to be asymmetric if it has four

different atoms or group attached to it .

If chiral molecules are mutually mirror image andnonsuperimposable Such space isomers are known as

enantiomer .A synonym is antipodes.



Enantiomer (two form of chiral)



Diastereomers

Diastereomers are compounds that are nonsuperimposable,nonmirror image isomers such compound has more than onechiral center in the molecules.

These isomers have different physical and chemical propertiesand thus differences in biological activity between such isomers

for example, Epedrine and pseudoephedrin



Enantiomers

Enantiomers

Diastereomers Diastereomers

A B

C D

6



Racemic mixtures

A mixture of equal amounts of two enantiomersthat is (+) and (-) forms is called a racemicmixture such a mixture is opticallyinactive(doesn‟t rotate the plane of polarised light

) b/c the two component rotate the plane ofpolariged light equally in opposite directions andcanceal one another.

For example, (+/-)Lactic acid



STEREOCHEMICAL TERMINOLOGY There are different systems to classify them

The first system of stereoisomer nomenclature is the d/l or (+)/-) systemthat is based on the direction in which the compound rotates plane-polarized light.

Enantiomers that rotate plane-polarized light to the right are termed asdextrarotatory which is indicated by d- or (+) and those that rotate light to

the left are termed as levorotatory and are designated by a l- or (-)-prefix.

A racemic mixture is indicated by either a d/l- or (+)/(-)-prefix. Thissystem has been used in chemistry for a long time, but the rotation ofplane-polarized light is not an absolute property . It is generally known

that the rotation depends on the solvent used

For example, chloramphenicol is dextrarotatory in alcohol butlevorotatory in ethyl acetate .

Contd.



The second and current system of stereoisomers is based

on the sequence of atoms or groups around its chiral centre. It is known as the Cahn- Ingold-Prelog system or (R,S)-system .It is the only system permitted to describe theabsolute configuration of compounds which have more thanone chiral centre.

Groups of atoms attached to the chiral centre are arrangedaccording to a sequence rule, in priority order of decreasingatomic number.

I > Br > Cl > F > OH > NH2 > CH3 > H

If the order of decreasing priority of the groups forming the

triangle is clockwise, then the configuration is called R-which stands for rectus.

If the order of decreasing priority of groups is counter-clockwise, then the configuration is called S- which stands

for sinister .



CHIROTECNOLOGY The process has been re-explored in recent years focusing onthe development of the „target specific drugs‟ through the

approach of enantiomeric drugs. Based on the pharmacologicalaspects of the drug and the receptor complexation,.

Trends in the pharmaceutical markets predict magnanimous

growth in single enantiomer drugs over racimates.

Worldwide sales of chiral drugs as single enantiomers areshowing steady growth at an average of 13 percent . Theprediction of the market shows substantial growth for the market

of the chiral drugs and sales estimates are made up to $200billion by 2008.



CHIRALITY and PHARMACOLOGY

In pharmacology, chirality is an important factor in drugefficacy.

About 56% of the drugs currently in use are chiral

compounds, and among them about 88% of chiral syntheticdrugs are used therapeutically as racemates.It means only12% drugs are marketed as pure single enantiomers ,so thatwe have to try to development of rest of racemates in asingle enantiomers.

Unfortunately, there are many racemic drugs where thestereospecificity of the metabolism and/or thepharmacodynamic effects of the enantiomers is not known



EFFECT OF CHIRALITY ONPHARMACOLOGICAL ACTIVITY

The drug interaction hypothesis was proposed by Beckett

The differences in biological activity b/w enantiomersdepends on their ability to react selectively at the receptorsite

In case of epinephrine ,only (-) isomer has the -OH groupin the correct orientation to allow perfect binding withreceptor

This explanation has been proposed as the reason forhigh pressor activity of (-) epinephrine ,whereas the (+)form of epinephrine shows less activity.



Pharmacokinetic and Pharmacodynamicimplications of chirality

All the pharmacokinetic processes, viz, absorption,distribution, metabolism and excretion may be influenced bychirality. for e.g., esomeprazole is more bioavailable thanracemic omeprazole.

The volume of distribution of levocitrizine has been shown tobe smaller than that of its dextro form , which is a positiveaspect in terms of both safety and efficacy.

Drug metabolizing enzyme systems are also subject to

stereos elective influences. Two isomers of a drug are oftenmetabolized at different rates. This may result in accumulationof the inactive enantiomer or rapid elimination of the active oneand vice versa.



Eudismic Ratio

• Terminology applies to a particular activity of a drug.

• Dual action drug the Eutomer of one activity may be theDistomer for another.

• Propranolol: S -enantiomer 40-100 fold more potent

than the R- as a β-adrenoceptor antagonist; similaractivity with respect to their membrane stabilisingproperties.

• Eudismic Ratios may also vary with receptor subtypes.

Noradrenaline: ER (R/S

): α1, 107; α2, 480.α-Methylnoradrenaline: ER (1R ,2S /1S ,2R ): α1,

60;α2, 550.



The pharmacodynamics implications of the conceptof chirality in drug activity stem from the fact that thebeneficial effects of a drug can reside in oneenantiomer.

Its counterpart enantiomer having either no activity

or less activity or antagonist activity against the activeenantiomer or completely separate beneficial oradverse activity from the active enantiomer.

The active and inactive enantiomers are referredto as „eutomer’ and „distomer’ respectively



Chiral switches

It involve development of single enantiomer fromracemic drug which is already marketed.

For example escitalopram, esomeprazole,

dexibuprofen, dexketoprofen, S-Ketamine ,laevocetirizine, laevofloxacin, (R, R)-methylphenidate,laevoleucovorin, levo-bupivacaine, and eszopiclone arethe examples of chiral switches because these drugs

were initially marketed as racemic mixtures.

Some of the chiral switches under development are:Dexloxiglumide, S-Doxazosin, R- and S- fluoxetine, R-

lipoic acid , S-oxybutynin and Dexnorcisapride.



SINGLE ENANTIOMER AND ITSADVANTASES

S-amlodipine CCB, long half-life , less metabolic load,and negligible pedal edemas.

S-atenolol —beta-1 blocker, and lesser side-effects onswitch-over from racemate to eutomer.

S-metoprolol , - avoiding the beta-2 blocking component,safer in poor metabolisers of CYP2D6, and avoids manydrug-drug interactions.

S-pantoprazole —more potent PPI and cytoprotective

R-ondansetron —

Clinically more potent component, doesnot prolong QTc interval, safer in children and elderly, andlesser side-effects racemate in poor metabolisers

All the above single enantiomer need half the racemate

dose.



A chiral HPLC-column for directresolution of enantiomers

CHIRAL-AGP is alpha1-acid glycoprotein (AGP).This is very stable protein.

That tolerates high concentrations of organic solvents,high and low pH, and high temperatures. The column is

used in the reversed-phase separates enantiomers ofan extremely broad range of drug compounds:

amines (primary, secondary, tertiary, and quaternary)

acids (strong and weak) nonprotolytes (amides, esters, alcohols, sulphoxides,

etc.)



Application Areas of chiralAGP

At pharmaceutical companies, hospitals,universities and chemical industry.

CHIRAL-AGP is used for the analysis ofenantiomer purity and for bioanalysis.

A growing application area is isolation ofpure enantiomers on semipreparativecolumns.

P i l d f i l



Potential advantages of singleenantiomer products

Less complex, more selective pharmacodynamicsprofile

Potential for an improved therapeutic index

Less complex pharmacokinetic profile

Reduced potential for complex drug interactions

Less complex relationship between plasma

concentration and effect



TRENDS IN THE DEVELOPMENTOF CHIRAL DRUGS

Drug chirality is now a major theme in the design, discovery,development, launching and marketing of new drugs.

Stereochemistry is an essential dimension in pharmacology.

Worldwide sales of chiral drugs in single-enantiomer forms

continue to grow.. The top ten single enantiomer blockbuster drugs (>US

$1 billion sales per year) are:

Atorvastatin calcium, Simvastatin , Pravastatin sodium ,

Paroxetine hydrochloride (CNS); Clopidogrel bisulfate ,Sertraline hydrochloride , Fluticasone propionate andsalmeterol xinafoate ; Esomeprazole magnesium ,Amoxicillin and Valsartan .



Recent Chiral Trends: USA

[[“In 2006, 80% of small molecule drugsapproved by the FDA were chiral and 75%

were single enantiomers.”

0

5

10

15

20

25

30

35

4045

50

2004 2003 2002 2001 2000

Achiral

Chiral Racemic

Chiral SingleStereoisomer

Others (peptides,proteins, polymers etc)



CHIRAL MOLECULES IN HYPERTENTION

Amlodipine exhibits chirality, i.e., it exists as two isomers.

Moreover, the receptor binding studies have shown that theS (-) isomer of amlodipine that has L-type calcium channelblocking activity.

The R (-) isomer exhibits a 1000-fold weaker calcium

channel blocking activity. Thus, the antihypertensive andantianginal activity of amlodipine can be attributed only to S(-) amlodipine, whereas the R (-) isomer can be regarded asinactive.

S (-) component is found to produce vasodilation byblocking the calcium channels in the arterial circulation. Thisproperty contributes to its antihypertensive effect.

On the other hand R(+) isomer produces venodilation andis responsible for the side effects associated with racemic

amlodipine.



Some drugs are developed

as pure enantiomers Defined as new single isomer chemicalentity (NSCE) such as enalapril, ramipril,

diltiazem, atorvastatin, simvastatin,pravastatin, clopidogrel, L-carnitine,laevodopa, d-penicillamine, levetiracetam,

and rivastigmine.



O

NH

OH

H

S

R- PROPRANOLOLS- PROPRANOLOL

O

NH

OHH

R



Chiral inversion



Chiral inversion

Chiral inversion is conversion of one enantiomerinto its mirror image. For example, the S form ofibuprofen is active but significant R (inactiveenantiomer) to S inversion takes place in the body.

Harmful intermediates are released during R-to-S conversion upon administration of racemate.

whereas administration of S-ibuprofen results inno such release of intermediates . This is thoughtto be the reason of enhanced safety of S-ibuprofen

over the racemate.



Racemic” Omeprazole is a very potent inhibitor of gastric acid

secretion.

omeprazole exhibits polymorphic metabolism, in a few individuals (3%among the Caucasian populations and 15-20% among Orientals) thatmetabolize omeprazole slowly (slow metabolizers)as compared to therest of the population (rapid metabolizers),

AstraZeneca developed the chiral switch drug esomeprazole (whichis the (S)-(-)-enantiomer of omeprazole) based on the therapeuticbenefit would be achieved by less inter-individual variation, (slowversus rapid metabolizers), and that average higher plasma levelswould provide higher dose efficiency in patients .

Esomeprazole was introduced as the magnesium trihydrate salt firstin Europe under the now famous trade name Nexium® .



Pharmaceutical industry's rolein chiral switches

Pharmaceutical companies are in the forefront ofpharmaceutical research and are responsible forproviding chirally pure products for clinical use.

However, the acceptance of any molecule(including chiral switches) would depend on itsadvantages .

Launching of chirally pure products from theracemate that has been already promoted requiresconsiderable amount of time and monetaryinvestments on its chemical separation and clinical

evaluation.

REFERENCES



REFERENCES www.japi.org VOL. 52 • MARCH 2004

J Indian Med Assoc 2007; 105: 177-8J Pharm Pharmaceut Sci (www.ualberta.ca/~csps)4(2):185-200, 2001

www.drugdiscoverytoday.com

www.leffingwell.com

Journal of Applied Biomedicine 2: 95.100, 2004

www. Express pharma pulse

http://www.indianjmedsci.org

www.fda.gov/cder/guidance/stereo.htm.

W.O.FOYE, principles of medicinal chemistry, 5th edition,

www.pubmed.gov

Indian Journal of Pharmacology 2006; 25: 73 –

77.

Chiral Pharmacology

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